There is an ongoing need in the pharmaceutical field to find effective ways of administering drugs that have low oral bioavailability. That is, a number of drugs are partially or completely metabolized in the liver and/or gastrointestinal tract, and cannot, therefore, be administered orally to achieve the desired therapeutic effect. Parenteral administration, i.e., injection, is one option, but not a route that many patients would find acceptable. Rectal and vaginal suppositories are also problematic from the standpoint of patient acceptance. Transdermal drug delivery has proved to be effective for a few drugs, but the vehicles and skin permeation enhancers typically required in transdermal systems can lead to skin irritation and/or sensitization, and the adhesive patches can be unpleasant to remove, leaving sensitive, discolored areas on the skin for some time after the patches are removed.
Buccal drug delivery, i.e., administration of a drug through the buccal mucosa, has also been described. Prior to the present invention, however, buccal drug delivery systems have proved to be problematic. A non-erodible backing layer is typically present that can lodge in the pharynx if a buccal tablet or patch is inadvertently swallowed. Prior buccal tablets or patches have also been relatively large and have tended to move about within a patient's mouth, both factors resulting in patient discomfort. More recently described buccal dosage forms are somewhat complicated to manufacture, insofar as distinct layers with different chemical and physical properties need to be made and incorporated into a single dosage form. See, for example, U.S. Pat. No. 5,346,701 to Heiber et al., which describes a bilayer tablet comprising a first, adhesive layer containing an adhesive polymer, a filler, an excipient, a lubricant, flavor, dye, etc., and an adjacent second layer containing drug, permeation enhancer, taste-masking agents, stabilizers, enzyme inhibitors, and possibly other components.
The present invention overcomes the disadvantages associated with prior buccal drug delivery systems, as will be discussed in detail herein. The buccal dosage unit of the invention is a highly effective, highly efficient, compact tablet that in its simplest form contains only drug and excipient. The dosage unit adheres well to the buccal mucosa, is small enough so as not to cause patient discomfort, and completely hydrolyzes within the mouth, i.e., gradually and completely bioerodes throughout the drug delivery period. The dosage unit may be used to administer any one of a number of pharmacologically active agents. One use of the buccal dosage units in the administration of steroidal agents, particularly androgenic agents, such as in male hormone replacement therapy, in male contraceptive compositions, in the treatment of androgen-responsive disorders, and in the treatment of male sexual dysfunction.
Androgens are the hormones that cause most of the masculinizing changes that occur in males during puberty. Harrison's Principles of Internal Medicine, 12.sup.th Edition (New York, N.Y.: McGraw Hill, Inc., 1991). Testosterone is secreted by the testis and adrenal gland and is the main androgen present in the plasma of men. See, e.g., Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9.sup.th Edition (New York, N.Y.: McGraw Hill, Inc., 1996). As explained in the aforementioned text, the concentration of testosterone in the plasma of human males is relatively high throughout several periods of life, including the period of embryonic development in which the male phenotypic differentiation takes place, the neonatal period, and during adult sexual life. Prior to puberty, concentrations of testosterone are in the plasma are low, on the order of 20 nanograms/deciliter (ng/dl) or less. In adults, plasma testosterone concentrations range from about 300 to 1000 ng/dl, and the rate of production is 2.5 to 11 mg per day. Approximately 40% of the testosterone is bound to sex hormone-binding protein and about 2% is free, or unbound; the remainder is bound to albumin and other proteins. Testosterone is secreted in a pulsatile manner, so that normal testosterone levels fluctuate within a circadian pattern during the course of a day. See, e.g., Goodman & Gilman's, supra.
At puberty, testosterone levels begin to rise in boys, reaching adult levels by the age of about seventeen. See, e.g., Harrison's Principles of Internal Medicine, supra. The rise in testosterone levels during puberty catalyzes a variety of anatomical and developmental changes, including maturation of the accessory organs of male reproduction, development of facial hair, regression of the scalp line, appearance of pubic hair, and increased growth of muscle and connective tissue. Altered testicular steroid levels can result from hypothalamic-pituitary disorders or testicular defects. For example, failure of the testis to develop or function, resulting in hypogonadism, may result from a deficiency of gonadotropin or from primary testicular failure. If hypogonadism occurs prior to puberty, development of secondary sexual characteristics will be impaired or absent. In the adult, hypogonadism results in osteopenia, regression of the prostate and seminal vesicles, reduction in the volume of semen, and loss of muscle mass, strength and vigor. Loss of steroid production also results in psychological depression and reduction or absence of the libido, both of which are associated with sexual dysfunction. See, e.g., Harrison's Principles of Internal Medicine, supra.
Testosterone is well absorbed after its oral administration but is quickly degraded during its passage through the liver and intestine. Therefore, it is not possible to achieve therapeutic blood levels of testosterone via oral administration. 17.alpha.-alkylated derivatives of testosterone can be administered orally and are resistant to hepatic degradation, but are not recommended for clinical use due to their high potential for hepatoxicity. Bhasin et al. (1997) J. of Clin. Endoc. and Met. 82(1):3. Transdermal delivery of testosterone has been described, but requires flux enhancement with skin permeation enhancers. As noted above, skin permeation enhancers frequently result in irritation and sensitization of the skin, and, with some enhancers, e.g., dimethyl formamide and dimethyl sulfoxide, the potential for toxicity is not insignificant. Accordingly, there remains a need in the art to provide a more effective method for administering androgenic agents such as testosterone.
Drug therapy involving buccal administration of steroid hormones has been described. For example, U.S. Pat. No. 4,755,386 to Hsiao et al. generally describes the buccal administration of various medicaments, including estrogens, progestins and androgens. The buccal tablets, weighing on the order of 50 mg, contain adhesive, disintegrant and excipient in addition to the active agent. Additionally, U.S. Pat. No. 4,764,378 to Keith et al. describes rapidly disintegrating dosage forms utilizing a combination of high and low molecular weight polyethylene glycols; the dosage forms, which are preferably 50 mg to 100 mg tablets, may be administered orally or through the buccal mucosa. Similarly, U.S. Pat. No. 5,135,752 to Snipes et al. describes buccal delivery systems containing polyethylene glycols of varying molecular weights for the delivery of methyl testosterone or estradiol (E.sub.2). In U.S. Pat. No. 4,877,774 to Pitha et al., crystalline complexes of steroid hormones and gamma-cyclodextrin are described for administration of steroids through mucosal tissue.
The buccal drug delivery systems of the present invention are, however, new and completely unsuggested by the art. Applicant's invention is premised on the discovery that a simple, compact, completely hydrolyzable buccal dosage unit, containing, in a preferred embodiment, only the pharmacologically active agent to be administered and an excipient, provides for highly efficient, highly effective drug delivery.